102 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc

Hematology Drugs in the Pipeline

HemOnc Today presents the most recent information about hematology drugs in the pipeline. Drugs listed here are in phase 2 or phase 3 development for a variety of indications. Clinicians can use this chart as a quick reference to learn about the status of those drugs that may be clinically significant to their practice. To view the entire chart online, go to www.Healio.com/HematologyPipeline.

Generic name (Brand name, Manufacturer) Indication(s) Development status

A6 peptide (Angstrom Pharmaceuticals) chronic lymphocytic , small lymphocytic lymphoma phase 2

AAV5-hFIX (UniQure Biopharma) hemophilia phase 2

ABC294640 (RedHill Biopharma) diffuse large B-cell lymphoma phase 2

(Eli Lilly) mantle cell lymphoma phase 2

abexinostat (Pharmacyclics) follicular lymphoma, mantle cell lymphoma phase 2

ABP 798 (Allergan/Amgen) non-Hodgkin’s lymphoma phase 3

ACP-196 (Acerta Pharma) B-cell malignancies (combination therapy), mantle cell lymphoma phase 2 READ PERSPECTIVE on this drug from Richard R. chronic lymphocytic leukemia phase 3 Furman, MD, on page 108.

ACP-319 (Acerta Pharma) B-cell lymphoma (combination therapy), chronic lymphocytic leukemia phase 2 (combination therapy) adeno-associated virus serotype 8 Factor IX gene therapy hemophilia B phase 2 (AskBio009, Baxalta) AEB071 (Novartis) diffuse large B-cell lymphoma (combination therapy for CD79-mutant or phase 2 ABC-subtype disease) AFM 13 (Affimed Therapeutics) Hodgkin’s lymphoma phase 2

alisertib (Millennium) peripheral T-cell lymphoma (relapsed or refractory) phase 3

ALT-803 (Altor BioScience) hematologic malignancies, phase 2

(Tolero Pharmaceuticals) acute myelogenous leukemia (relapsed or refractory) phase 2

acute myelogenous leukemia (first-line) phase 3 andexanet alfa (Portola Pharmaceuticals) Factor Xa inhibitor antidote phase 3

antihemophilic factor [recombinant], porcine sequence (Obizur, Baxalta) hemophilia A, hemophilia B phase 3

AR-42 (Arno Therapeutics) hematologic malignancies phase 2

ASP2215 (Astellas) acute myelogenous leukemia phase 3

AST-VAC1 (Asterias Biotherapeutics) acute myelogenous leukemia phase 2

AT7519 (Astex Pharmaceuticals) multiple myeloma phase 2

for injection (Vidaza, Celgene) acute myelogenous leukemia (post-induction maintenance) phase 3

BAX 111 (Baxalta) von Willebrand’s disease phase 3

BAX 335 (Baxalta) Factor IX gene therapy in adults with hemophilia B phase 2

BAX 555 (Baxalta) sickle cell disease phase 2

BAX 855 (Baxalta) hemophilia A phase 3

BB305 (Lentiglobin, Bluebird Bio) beta-thalassemia, sickle cell disease phase 2

BC8-I-131 construct (Iomab-B, Actinium Pharmaceuticals) hematopoietic stem cell transplantation in acute lymphoblastic leukemia phase 2

(Treanda, Teva Oncology) mantle cell lymphoma phase 2

betrixaban (Portola Pharmaceuticals) Factor Xa inhibitor phase 3

BI 695500 (Boehringer Ingelheim) follicular lymphoma (first-line) phase 3

BI 836858 (Boehringer Ingelheim) phase 2

birinapant (TetraLogic Pharmaceuticals) cutaneous T-cell lymphoma, myelodysplastic syndrome phase 2

Bismab-A (Actinium Pharmaceuticals) acute myelogenous leukemia phase 2

BL-8040 (BioLineRx) acute myelogenous leukemia (combination therapy) phase 2 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc 103

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

(Blincyto, Amgen) acute lymphoblastic leukemia (relapsed or refractory Philadelphia chromo- phase 2 some-positive disease), diffuse large B-cell lymphoma

acute lymphoblastic leukemia (relapsed or refractory disease) phase 3 (Velcade, Millennium) diffuse large B-cell lymphoma phase 2

mantle cell lymphoma (first-line) phase 3 bosutinib (Bosulif, ) chronic myeloid leukemia (first-line) phase 3

BP-100-1-01 (Bio-Path Holdings) acute myelogenous leukemia phase 2

BPX-501 (Bellicum Pharmaceuticals) acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lym- phase 2 phocytic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma (Adcetris, Seattle Genetics) diffuse large B-cell lymphoma (CD30-positive disease), Hodgkin’s lymphoma phase 2 (first-line therapy for elderly patients)

cutaneous T-cell lymphoma (relapsed CD30-positive disease), Hodgkin’s lym- phase 3 phoma (first-line), Hodgkin’s lymphoma (post-transplant relapse prevention), T-cell lymphoma (CD30-positive mature disease) BVD-523 (BioMed Valley Discoveries) acute myelogenous leukemia, myelodysplastic syndrome phase 2

calaspargase pegol (Baxalta) acute lymphoblastic leukemia phase 3

(Kyprolis, Onyx Pharmaceuticals) multiple myeloma (first-line therapy) phase 3

carlecortemcel-L (StemEx; Gamida Cell and Teva) hematologic malignancies phase 3

CC-486 (Celgene) myelodysplastic syndrome (post failure) phase 2

acute myelogenous leukemia (post-induction maintenance), myelodysplastic phase 3 syndrome (lower-risk disease) CDX-301 (Celldex Therapeutics) B-cell lymphoma, stem cell transplantation in hematologic malignancies phase 2

cerdulatinib (Portola Pharmaceuticals) chronic lymphocytic leukemia, non-Hodgkin’s lymphoma phase 2

CMD-003 (Cell Medica) EBV-positive, extranodal natural killer T-cell lymphoma phase 2

CNDO-109 (Fortress Biotech) acute myelogenous leukemia phase 2

coagulation Factor VIIa recombinant (LR769, rEVO Biologics) hemophilia A, hemophilia B phase 3

coltuximab ravtansine (Immunogen) diffuse large B-cell lymphoma phase 2

(Bayer) diffuse large B-cell lymphoma phase 2

non-Hodgkin’s lymphoma phase 3 cord blood stem cell therapy (NiCord, Gamida Cell) hematologic malignancies phase 2

crenolanib (Arog Pharmaceuticals) acute myelogenous leukemia (newly diagnosed disease, maintenance phase 2 therapy after bone marrow transplantation)

acute myelogenous leukemia (relapsed or refractory disease) phase 3 CTL019 (Novartis) acute lymphoblastic leukemia phase 2

CX-01 (Cantex Pharmaceuticals) acute myelogenous leukemia phase 2

: (CPX-351, Celator Pharmaceuticals) acute myelogenous leukemia, myelodysplastic syndrome (high-risk disease), phase 2 pre-conditioning before hematopoietic stem cell transplantation dabigatran etexilate (Pradaxa, Boehringer Ingelheim) stroke prevention in patients with nonvalvular oral anticoagulation phase 3

damoctocog alfa pegol (Bayer) hemophilia phase 3

(Janssen) multiple myeloma (first-line therapy; first-line combination therapy; combi- phase 3 nation therapy for recurrent or relapsed disease) READ PERSPECTIVE on this drug from Paul G. Richardson, MD, on page 108, and Ruben Niesvizky, MD, on page 108.

darbepoetin alfa (Aranesp, Amgen) myelodysplastic syndrome (low-risk disease) phase 3

darinaparsin (SP-02, Solasia Pharma) peripheral T-cell lymphoma phase 2

dasatinib (Sprycel, Bristol-Myers Squibb) leukemia (pediatric patients) phase 2

denosumab (Xgeva, Amgen) prevention of skeletal-related events in multiple myeloma phase 3 104 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

DFP-10917 (Delta-Fly Pharma) acute lymphoblastic leukemia, acute myelogenous leukemia phase 2

DI-Leu16-IL2 (Alopexx Oncology) non-Hodgkin’s lymphoma phase 2

DKN-01 (HealthCare Pharmaceuticals) multiple myeloma phase 2

(AbbVie and Infinity Pharmaceuticals) non-Hodgkin’s lymphoma (refractory indolent disease) phase 2

chronic lymphocytic leukemia (relapsed or refractory disease), follicular phase 3 lymphoma (previously treated disease) E6201 (Strategia Therapeutics) hematologic malignancies phase 2

(AbbVie and Bristol-Myers Squibb) multiple myeloma (combination therapy, second-line) phase 2 READ PERSPECTIVE on this drug from Ruben multiple myeloma (combination therapy, first-line; combination therapy for phase 3 Niesvizky, MD, on page 108. relapsed or refractory disease) eltrombopag (Promacta, Novartis) myelodysplastic syndrome phase 2

entospletinib (Gilead Sciences) hematologic malignancies phase 2

epratuzumab (Immunomedics) leukemia, lymphoma phase 2

EPZ-6438 (Epizyme) non-Hodgkin’s lymphoma phase 2

ERY-ASP (Erytech Pharma) acute lymphoblastic leukemia (adults) phase 2

everolimus (Afinitor, Novartis) diffuse large B-cell lymphoma phase 3

FF-10501 (Strategia Therapeutics and Fujifilm Pharmaceuticals USA) hematologic malignancies phase 2

filanesib (Array BioPharma) multiple myeloma phase 2

ganetespib (Synta Pharmaceuticals) acute myelogenous leukemia phase 2

GC1101C (Green Cross) hemophilia A phase 3

glasdegib (PF-04449913, Pfizer) acute myelogenous leukemia, myelodysplastic syndrome phase 2

GO-203-2c (Genus Oncology) acute myelogenous leukemia (relapsed or refractory disease) phase 2

GP2013 (Novartis) chronic lymphocytic leukemia, non-Hodgkin’s lymphoma

guadecitabine (SGI-110, Astex Pharmaceuticals) hematologic malignancies phase 3

HSC835 (Novartis) hematologic malignancies in single umbilical cord blood transplantation phase 2

HSV-Tk (MolMed) acute leukemia (high-risk disease) phase 3

human-cl rhFVIII (Octapharma) hemophilia A phase 3

ibrutinib (Imbruvica; Pharmacyclics and Janssen) chronic lymphocytic leukemia (single-agent therapy for treatment-naive phase 3 patients; combination therapy for relapsed or refractory disease), diffuse large B-cell lymphoma (combination therapy for newly diagnosed non- germinal center B-cell subtype), mantle cell lymphoma (single-agent therapy for relapsed or refractory disease; combination therapy for treatment-naive patients), non-Hodgkin’s lymphoma (combination therapy for relapsed or refractory disease), Waldenstrom’s macroglobulinemia (combination therapy for previously treated adults) (Gilead Sciences) non-Hodgkin’s lymphoma (first-line therapy for indolent disease) phase 2

chronic lymphocytic leukemia (first-line treatment; relapsed or refractory phase 3 disease), non-Hodgkin’s lymphoma (relapsed or refractory indolent disease) imetelstat (Janssen) myelofibrosis phase 2

IMO-8400 (Idera Pharmaceuticals) diffuse large B-cell lymphoma, Waldenstrom’s macroglobulinemia phase 2

Imprime PGG (Biothera) chronic lymphocytic leukemia (combination therapy for first-line treatment phase 2 of high-risk disease), non-Hodgkin’s lymphoma (combination therapy for second- and third-line treatment of advanced indolent disease) INCB39110 (Incyte) B-lymphoid malignancies phase 2

INCB40093 (Incyte) B-cell malignancies phase 2 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc 105

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

INCB52793 (Incyte) hematologic malignancies phase 2

(Biotest Pharmaceuticals) multiple myeloma phase 2

(Pfizer) acute lymphoblastic leukemia phase 3

intravenous immunostimulant (Imprime PGG, Biothera) chronic lymphocytic leukemia (first-line treatment of high-risk disease) phase 2

(Sanofi) multiple myeloma phase 2

(Millennium/Takeda Oncology) follicular lymphoma (relapsed or refractory) phase 2

amyloidosis, myeloma (treatment-naive disease; relapsed or refractory disease) phase 3 JCAR014 (Juno Therapeutics) acute lymphoblastic leukemia, chronic lymphocytic leukemia (refractory phase 2 disease), non-Hodgkin’s lymphoma JCAR015 (Juno Therapeutics) acute lymphoblastic leukemia phase 2

JCAR017 (Juno Therapeutics) leukemia phase 2

JTCR016 (Juno Therapeutics) acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic phase 2 syndrome KB004 (KaloBios Pharmaceuticals) hematologic malignancies (EphA3-positive disease) phase 2

KTE-C19 CAR (Kite Pharma) diffuse large B-cell lymphoma phase 2

B-cell lymphoma phase 3 lenalidomide (Revlimid, Celgene) chronic lymphocytic leukemia (maintenance therapy, second-line), diffuse phase 3 large B-cell lymphoma (maintenance therapy), diffuse large B-cell lymphoma (first-line therapy for ABC subtype), follicular lymphoma (first-line), indolent lymphoma (relapsed or refractory disease), multiple myeloma (maintenance therapy), myelodysplastic syndrome (non-deletion 5q) Ac-225 (Actinium Pharmaceuticals) acute myelogenous leukemia (first-line) phase 2

long-acting fusion protein linking recombinant coagulation Factor hemophilia B phase 3 IX with recombinant albumin (rIX-FP, CSL Behring) luspatercept (ACE-536; Acceleron Pharma and Celgene) beta-thalassemia, myelodysplastic syndrome phase 3

LY2928057 (Eli Lilly) anemia phase 2

marizomib (Triphase Accelerator) multiple myeloma (relapsed or refractory disease) phase 2

MEDI-551 (MedImmune) chronic lymphocytic leukemia, diffuse large B-cell lymphoma phase 2

- conjugate (Immunomedics) acute lymphoblastic leukemia, non-Hodgkin’s lymphoma phase 2

MK-8628 (Merck) hematologic malignancies phase 2

mocetinostat (Mirati Therapeutics) diffuse large B-cell lymphoma, myelodysplastic syndrome phase 2

MOD-5014 (Opko Biologics) hemophilia A, hemophilia B phase 2

mogamulizumab (Kyowa Hakko Kirin) T-cell leukemia and lymphoma (adults) phase 2

cutaneous T-cell lymphoma phase 3 molidustat (Bayer) anemia phase 2

momelotinib (Gilead Sciences) myelofibrosis phase 3

MOR208 (MorphoSys) acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin’s phase 2 lymphoma (MedImmune) acute lymphoblastic leukemia (pediatric patients) phase 2

hairy cell leukemia phase 3 N8-GP (NN7088, Novo Nordisk) hemophilia A phase 3

N9-GP (NN7999, Novo Nordisk) hemophilia B phase 3

nilotinib (Tasigna, Novartis) acute lymphoblastic leukemia (pediatric patients), chronic myeloid leukemia phase 2 (pediatric patients)

chronic myeloid leukemia (treatment-free remission) phase 3 106 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

(Opdivo, Bristol-Myers Squibb) diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin’s lymphoma phase 2 READ PERSPECTIVE on this drug from Stephen M. Ansell, MD, PhD, on page 109.

NNC 0129-0000-1003 (Novo Nordisk) hemophilia A phase 3

NY-ESO-1/LAGE-1–specific T cells (Adaptimmune) multiple myeloma (advanced disease) phase 2

(Gazyva, Genentech/Roche) chronic lymphocytic leukemia (combination therapy for first-line treatment; phase 3 combination therapy for relapsed or refractory disease), diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma (first-line therapy for indolent disease; refractory indolent disease) (Arzerra, Novartis) chronic lymphocytic leukemia (maintenance therapy and relapsed disease), phase 3 non-Hodgkin’s lymphoma (relapsed or refractory disease) Oncoquest-L (XEME Biopharma) follicular lymphoma phase 2

(Onyx Pharmaceuticals) multiple myeloma (monotherapy), Waldenstrom’s macroglobulinemia phase 2 (monotherapy) (TRU-116, Emergent BioSolutions) chronic lymphocytic leukemia phase 2

OVI-123 (OncoVista Innovative Therapies) TdT-positive leukemia phase 2

pacritinib (Baxalta and CTI Biopharma) acute myelogenous leukemia (relapsed disease) phase 2

myelofibrosis phase 3 (Oncaspar, Baxalta) acute myelogenous leukemia phase 2

acute lymphoblastic leukemia phase 3 (Keytruda, Merck) Hodgkin’s lymphoma phase 2 READ PERSPECTIVE on this drug from Stephen M. Ansell, MD, PhD, on page 109.

PF-05280586 (Pfizer) follicular lymphoma (first-line therapy) phase 3

pidilizumab (Medivation) diffuse large B-cell lymphoma phase 2

PIM447 (Novartis) multiple myeloma phase 2

(Pixuvri, CTI BioPharma) non-Hodgkin’s lymphoma (combination therapy for second-line treatment of phase 3 aggressive disease) PKC412 (Novartis) acute myelogenous leukemia phase 3

plitidepsin (PharmaMar) multiple myeloma (combination therapy), T-cell lymphoma phase 2

multiple myeloma (relapsed or refractory disease) phase 3 PM01183 (PharmaMar) acute leukemia phase 2

PNT2258 (ProNAi Therapeutics) diffuse large B-cell lymphoma (relapsed or refractory disease), non-Hodgkin’s phase 2 lymphoma (relapsed or refractory disease) (RG7596, Genentech/Roche) diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma phase 2

ponatinib (Iclusig, Ariad Pharmaceuticals) acute lymphoblastic leukemia (Philadelphia chromosome-positive disease) phase 2

pracinostat (MEI Pharma) acute myelogenous leukemia (first-line), myelodysplastic syndrome (first-line phase 2 treatment and refractory disease) PRI-724 (PRISM Pharma) acute myelogenous leukemia, chronic myeloid leukemia phase 2

PRM-151 (Promedior) myelofibrosis phase 2

PVX-410 (OncoPep) multiple myeloma (smoldering) phase 2

quizartinib (Ambit Biosciences) acute myelogenous leukemia (relapsed or refractory disease) phase 3

recombinant Factor VIIa fusion protein (CSL689, CSL Behring) hemophilia A phase 2

hemophilia B phase 3 recombinant Factor VIII (Bay81-8973, Bayer) hemophilia A phase 3

recombinant Factor VIII-single chain (CSL Behring) hemophilia A phase 3

recombinant Factor IX (Bax 326, Baxalta) hemophilia B phase 3 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc 107

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

recombinant von Willebrand Factor (Baxalta) von Willebrand disease phase 3

regadenoson (Lexiscan, Astellas) sickle cell anemia phase 2

rexlemestrocel-L (Mesoblast) hematologic malignancies (bone marrow regeneration in patients undergo- phase 3 ing bone marrow transplantation) ricolinostat (Acetylon Pharmaceuticals) lymphoma, multiple myeloma (relapsed or refractory disease) phase 2

rigosertib (Onconova Therapeutics) myelofibrosis (combination therapy for first-line treatment of high-risk disease) phase 2 READ PERSPECTIVE on this drug from Azra Raza, acute myelogenous leukemia (first-line treatment of high-risk disease), my- phase 3 MD, on page 109. elodysplastic syndrome (post-HMR, high-risk disease) rivaroxaban (Xarelto, Bayer) venous thromboembolism prevention phase 3

rivipansel (GMI-1070, GlycoMimetics) vaso-occlusive crisis associated with sickle cell disease phase 3

(Istodax, Celgene) peripheral T-cell lymphoma (first-line) phase 3

RP-323 (Rich Pharmaceuticals) acute myelogenous leukemia, myelodysplastic syndrome phase 2

Sanguinate (Prolong Pharmaceuticals) sickle cell anemia phase 2

sapacitabine (Cyclacel Pharmaceuticals) myelodysplastic syndrome phase 2

acute myelogenous leukemia phase 3 SD-101 (Dynavax Technologies) B-cell lymphoma phase 2

selinexor (Karyopharm Therapeutics) multiple myeloma (combination therapy) phase 2 READ PERSPECTIVE on this drug from John P. acute myelogenous leukemia, diffuse large B-cell lymphoma, multiple my- phase 3 Leonard, MD, on page 109. eloma (monotherapy), Richter’s transformation SG2000 (Spirogen) acute myelogenous leukemia, chronic lymphocytic leukemia phase 2

SGI-110 (Astex Pharmaceuticals) myelodysplastic syndrome phase 2

acute myelogenous leukemia phase 3 SGN-CD19A (Seattle Genetics) diffuse large B-cell lymphoma phase 2

SGX301 (Soligenix) cutaneous T-cell lymphoma phase 2

SHAPE (TetraLogic Pharmaceuticals) cutaneous T-cell lymphoma phase 2

(Sylvant, Janssen) multiple myeloma (smoldering) phase 2

simvastatin (Zocor, Merck) sickle cell disease phase 2

SL-401 (Stemline Therapeutics) acute myelogenous leukemia (relapsed or refractory disease), blastic plasmacytoid phase 2 dendritic cell neoplasm, myeloproliferative neoplasms (advanced high-risk disease) sonidegib (Odomzo, Novartis) acute leukemia phase 2

sotatercept (Acceleron and Celgene) anemia, multiple myeloma, myelofibrosis phase 2

TAS-120 (Taiho Oncology) multiple myeloma (advanced disease) phase 2

TG-1101 (TG Therapeutics) chronic lymphocytic leukemia (monotherapy), non-Hodgkin’s lymphoma phase 2

chronic lymphocytic leukemia (combination therapy), mantle cell lymphoma phase 3 (combination therapy) tosedostat (CTI BioPharma) acute myelogenous leukemia, myelodysplastic syndrome phase 2

TSR-011 (TESARO Inc.) lymphoma phase 2

TZ101 (Targazyme) cord blood stem cell transplantation in hematologic malignancies phase 2

(Immunomedics) non-Hodgkin’s lymphoma phase 2

(AbbVie and Genentech) acute myelogenous leukemia, chronic lymphocytic leukemia (refractory disease phase 2 with 17p-deletion), diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma

chronic lymphocytic leukemia (first-line treatment; combination treatment for phase 3 relapsed, refractory disease) vepoloxamer (MST-188, MAST Therapeutics) sickle cell disease phase 3 108 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc

Hematology Drugs in the Pipeline

Generic name (Brand name, Manufacturer) Indication(s) Development status

sulfate liposome injection (Marqibo, Spectrum acute lymphoblastic leukemia (first-line treatment of elderly patients with phase 3 Pharmaceuticals) Philadelphia chromosome-negative disease), non-Hodgkin’s lymphoma (first-line therapy for aggressive disease) VLX1570 (Vivolux) multiple myeloma phase 2

volasertib (Boehringer Ingelheim) acute myelogenous leukemia phase 3

vosaroxin (Qinprezo, Sunesis) acute myelogenous leukemia, myelodysplastic syndrome phase 2

WT-1 vaccine (STELLAS Life Sciences) hematologic malignancies phase 2

Information in this chart was compiled from the Pharmaceutical Research and Manufacturers of America, NIH (www.clinicaltrials.gov), corporate websites and the databases of HemOnc Today. The publisher or editors do not assume responsibility for any errors or omissions.

PERSPECTIVE: DARATUMUMAB PERSPECTIVE: ACP-196 If I had to pick the most exciting new drug to emerge in this extraor- One of the new agents that I’m most excited about is ACP-196 dinarily productive year for multiple myeloma, I would suggest dara- (Acerta Pharma), which is a second-generation inhibitor of Bruton’s tumumab (Janssen and Genmab) as one of the most promising and tyrosine kinase (BTK). ACP-196 binds to BTK at the same amino acid arguably transformative in the long term, when added to the ongoing residue as ibrutinib (Imbruvica; Pharmacyclics, Janssen) does, but it impact of proteasome inhibition — such as with bortezomib (Velcade; is more selective in its binding. Although ibrutinib targets BTK, it also Millennium/Takeda) and carfilzomib (Kyprolis, Onyx) — and immuno- binds to eight other enzymes. The most common side effects seen with modulatory drugs, such as thalidomide (Thalomid, Celgene), lenalido- ibrutinib — namely diarrhea, bruising and atrial fibrillation — are the mide (Revlimid, Celgene) and pomalidomide (Pomalyst, Celgene). results of these off-target effects. ACP-196, given its better selectivity, Paul G. Richardson Daratumumab is a very potent , with a com- Richard R. Furman has not been associated with diarrhea, bruising or atrial fibrillation. pletely new mechanism of action, and we have been privileged to be on the forefront of its My hope is that we not only have an agent that works incredibly well in CLL, but now clinical development from phase 1 through phase 3 as part of an international team. have an excellent agent that works incredibly well with no . That is really the Holy Targeting CD38 with this very well-engineered antibody has proven highly successful Grail of what we would hope to achieve in terms of treatment for our patients. and has been validated in subsequent studies by other antibodies in the same class. Most — Richard R. Furman, MD importantly, not only has daratumumab proven feasible to administer and active as a single Weill Cornell Medicine agent — as we very recently published in The New England Journal of Medicine — but, when NewYork-Presbyterian Hospital combined with other drugs, its efficacy is particularly impressive. Disclosure: Furman reports consultant and speakers bureau roles with Pharmacyclics. Daratumumab as a single agent generates major clinical responses in about a third of otherwise highly refractory patients. When combined with lenalidomide, the response rates jump dramatically. In fact, close to 80% to 90% of patients with relapsed/refractory disease appear to respond, and I think this promises enormous benefit for patients in vari- PERSPECTIVE: ELOTUZUMAB, DARATUMUMAB ous settings in the future, such as part of upfront treatment as well as maintenance. The most exciting findings in the pipeline for myeloma appear to It is important to recognize that elotuzumab (AbbVie and Bristol-Myers Squibb) is another be related to immune-regulation drugs. The most recent published very promising advance in the monoclonal antibody space that has been validated in the manuscripts emphasize elotuzumab (AbbVie, Bristol-Myers Squibb), a phase 3 setting and — in my opinion — will be approved by the regulatory authorities hope- SLAMF7 antibody, and daratumumab (Janssen), an anti-CD38 antibody. fully this year, with great potential to meaningfully and further improve patient outcome. A recent randomized trial compared elotuzumab, lenalidomide I think the fact that daratumumab not only has single-agent activity but — just like (Revlimid, Celgene) and dexamethasone with a control regimen of le- elotuzumab — is highly active in combination with a different target, and has multiple nalidomide and dexamethasone in patients with relapsed/refractory effects that are beyond the immuno-oncologic spectrum alone, is especially compelling. myeloma. It was very encouraging to find the infusion therapy was not Two other new agents warrant mention. The approval of (Farydak, Novartis) Ruben Niesvizky toxic and that elderly patients can receive this therapy without any ma- this year as a first-in-class molecule in the area of histone deacetylase inhibition is a milestone. jor infusion reactions. In my view, next-generation inhibitors show great promise. Second, the results of ixazomib Further, although single-agent activity has not been demonstrated, prolongation of (Takeda) in combination with lenalidomide and dexamethasone in relapsed, refractory my- PFS has been shown for the elotuzumab group, particularly in patients who are naive to eloma in the TOURMALINE study are very exciting for an all-oral approach, with excellent ef- lenalidomide. I can foresee using elotuzumab in combination with lenalidomide and dexa- ficacy and favorable tolerability. For the first orally bioavailable to enter methasone earlier in the disease — particularly in those patients who have not received phase 3 studies, these results — which will be fully shared as an oral presentation at the ASH lenalidomide — and that we will achieve long-term results, especially among the elderly or Annual Meeting and Exposition in December — are especially provocative. the infirm, for whom multiple comorbidities would preclude other types of therapy. With all of the above in mind, and a true plethora of important and very good options Randomized trials of daratumumab are ongoing. The New England Journal of Medicine emerging for our patients in a record-breaking year, I would propose daratumumab as the published results from a frontline phase 2 regimen of daratumumab that showed staggering most promising single agent. Its unique mechanism of action and striking activity as mono- responses, particularly in patients who have gone through several lines of therapy, including therapy, its efficacy in combination and its manageable safety profile provide a vital new ther- proteasome inhibitors and immunomodulators. This is the first monoclonal antibody that has apeutic approach for this otherwise very challenging disease. shown high single-agent activity, even in relapsed/refractory patients. — Paul G. Richardson, MD I can foresee seeing this agent move forward in the frontline and, more importantly, in HemOnc Today Editorial Board member combinations. Dana-Farber Cancer Institute — Ruben Niesvizky, MD Harvard Medical School Weill Cornell Medicine Disclosure: Richardson reports advisory roles with Bristol-Myers Squibb, NewYork-Presbyterian Hospital Celgene, Genmab, Janssen and Millennium/Takeda. Disclosure: Niesvizky reports research support from Bristol-Myers Squibb and Johnson & Johnson. HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc 109

Hematology Drugs in the Pipeline

HemOnc Today asked key opinion leaders to offer perspective about hematology drugs in the pipeline they believe have the potential to change practice.

PERSPECTIVE: PEMBROLIZUMAB, NIVOLUMAB PERSPECTIVE: RIGOSERTIB The treatment approach that I believe holds the greatest promise Myelodysplastic syndrome (MDS) is a heterogeneous group of to fill an unmet need and make a very significant impact on patients bone marrow disorders characterized by ineffective hematopoiesis in general is PD-1 blockade with either pembrolizumab (Keytruda, and increased risk for developing into . Pa- Merck) or nivolumab (Opdivo, Bristol-Myers Squibb), in patients with tients with MDS who receive repeated blood transfusions also are at Hodgkin’s lymphoma. This treatment has already demonstrated high risk for chronic iron overload. response rates in previously treated patients. Looking to the future, The last drug to be approved for MDS was 10 years ago. I am par- using these agents in combination with earlier-phase approaches is ticularly encouraged by the responses to a small molecule inhibitor likely to make a substantial impact on how we treat patients. of cellular signaling called rigosertib (Onconova Therapeutics) in Stephen M. Ansell — Stephen M. Ansell, MD, PhD Azra Raza both lower-risk and higher-risk MDS patients. HemOnc Today Editorial Board member Rigosertib acts as a RAS mimetic. The main activity is mediated through the RAS- Mayo Clinic binding domain (RBD) found in many effector proteins, exemplifying a novel approach Rochester, Minnesota to block the interactions between RAS and its RBD-containing targets, such as PI3 kinase, Disclosure: Mayo Clinic receives research funding from Bristol-Myers Squibb pathways implicated in the pathogenesis of MDS. and Merck for clinical trials that involve pembrolizumab and nivolumab. Rigosertib is available as an IV infusion and as oral capsules. More than 1,200 patients have been treated in clinical trials worldwide. Published results have shown that rigosert- ib has the potential to provide survival benefit to patients with high-risk MDS and to im- prove hematological function in patients with low-risk MDS. PERSPECTIVE: SELINEXOR The global phase 3 INSPIRE trial — currently enrolling patients — will evaluate IV ri- One of the new agents in clinical trials that I think is very inter- gosertib in patients with high-risk MDS who progressed on or failed to respond to a hypo- esting is a drug called selinexor (Karyopharm Therapeutics), a se- methylating agent. Oral rigosertib is being developed as a single agent for the treatment lective inhibitor of nuclear export. It interferes with trafficking of of low-risk MDS, and in combination with azacitidine (Vidaza, Celgene) for the treatment molecules in and out of the nucleus. The net effect of this drug is of high-risk MDS and AML. that it affects growth signals and results in antiproliferative effects — Azra Raza, MD in a variety of different lymphomas. Columbia University This is exciting, in part, because it is an oral agent that Disclosure: Raza reports no relevant financial disclosures. seems — at least at this point — to have activity in highly aggres- John P. Leonard sive lymphomas, such as large-cell lymphoma, Richter’s transfor- mation and double-hit lymphoma. These subtypes have very little in the way of good therapies for the relapsed setting. Most novel agents have limited efficacy there. The idea that this drug potentially has activity in these aggressive relapsed lymphoma sub- types is quite exciting. It may offer a new option, and we — along with others — are VIEW THIS CHART ONLINE now looking at it in combination with (Rituxan; Genentech, Biogen Idec) and To view HemOnc Today’s Hematology SCAN THE CODE TO in combination with to see if we can really make an impact in what are Drugs in the Pipeline chart, or to offer a view this chart and among the highest unmet need areas of lymphoma. comment about the agent in phase 2 or accompanying perspectives — John P. Leonard, MD phase 3 development you believe offers the online at Weill Cornell Medicine greatest potential to change practice, go to Healio.com/HemOnc. NewYork-Presbyterian Hospital www.Healio.com/HematologyPipeline. Disclosure: Leonard reports no relevant financial disclosures.